Role of sigma receptors in ethanol reinforcement

摘要：申请书为Valentina Sabino博士提出了职业发展计划， 药理学培训的博士后研究员致力于研究职业生涯中的乙醇成瘾，目的是 去了解它的分子基础申请人将由乔治库布博士指导， 神经科学方法和酒精中毒的动物模型，并由Pietro Sanna博士共同指导， 免疫组织化学和分子技术。该项目将在斯克里普斯研究中心进行， 研究所在圣地亚哥丰富的神经科学社区，关注西格玛受体，独特的哺乳动物 调节其他神经递质系统并在边缘脑中大量表达的结合位点 结构.药理学研究表明，σ受体调节可卡因的作用， 冰毒最近，也已经提出σ受体调节神经元的激发特性。 乙醇，与人类酒精中毒中σ受体多态性的发现一致。直到最近， 然而，对σ受体系统的理解受到缺乏特异性， 亚型选择性配体或缺乏σ受体亚型的突变小鼠模型。而且 σ受体在自愿摄入或自我施用乙醇中的作用是未知的。本 多学科应用使用行为学、药理学和分子技术来确定 具有亚型特异性的sigma受体对乙醇奖赏和抑制的调节作用 过度消耗乙醇的模型。将在具体研究中研究过量乙醇摄入的两种模型 目的1和3 --通过遗传选择的酒精偏好大鼠和孤僻的远系繁殖大鼠产生依赖性 在慢性、间歇性暴露于乙醇蒸汽期间，强调正强化和负强化 乙醇的特性。乙醇自我给药将被调节（在 特异性目的1），通过给予新的α受体配体，和在分子上（在特异性目的2中）， 通过使用o-1受体KO小鼠。长期暴露于乙醇和先天性 将研究乙醇对离散边缘脑区域中O受体蛋白表达的偏好， 具体目标3。相关性：该项目将定义一种药物的生理和潜在治疗相关性。 在酒精滥用和依赖的调节性受体系统中的特征不足。

Summary: The application proposes a career development plan for Dr. Valentina Sabino, a pharmacologically-trained post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its molecular basis. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of alcoholism and co-mentored by Dr. Pietro Sanna in immunohistochemical and molecular techniques. The project, to be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego, concerns sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtype-selective ligands or of mutant mouse models that lack sigma receptor subtypes. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacologic, and molecular techniques to determine the modulatory role of sigma receptorswith subtype specificity on ethanol reward and reinforcementin distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethanol self-administration will be pharmacologically modulated (in Specific Aim 1), through the administration of novel a receptor ligands, and molecularly (in Specific Aim 2), through the use of o-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on o receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3. Relevance: The project will define the physiologic and potential therapeutic relevance of an undercharacterized modulatory receptor system for alcohol abuse and dependence.